Block 3 - obesity/adipokine action/hypertension in the metabolic syndrome (L11-12)

Question 1

What is the function of adiponectin?

Answer 1

insulin sensitizer and anti-inflammatory

Question 2

How do adiponectin levels correlate to body fat, insulin, and insulin sensitivity?

Answer 2

body fat and fasting insulin: negative correlation, as they increase adiponectin decreases

insulin stimulated glucose disposal: positive correlation, it increases as adiponectin increases

Question 3

Describe the structure of adiponectin

Answer 3

• 30 kDa glycoprotein produced from white fat cells
• aggregates in plasma as either low molecular weight forms (trimers and hexamers) or high molecular weight forms (12-18mers)
• the globular form, a proteolytic cleavage product, exists and can have biological actions

Question 4

Where does most adopinectin come from?

Answer 4

small adipocytes (higher rate) rather than large adipocytes (lower rate)

Question 5

How is adiponectin transported?

Answer 5

• in the plasma, bound to a binding globulin like albumin
• transendothelial transport at target tissues is regulated, and may be defective in insulin resistant states

Question 6

The two main adiponectin receptors are called —- and —- and their structure is…

Answer 6

AdipoR1 and AdipoR2
seven membrane spanning regions

Question 7

There is a third adiponectin receptor that has a different structure. What is it, and how is the structure different?

Answer 7

T-cadherin has no cytoplasmic region

Question 8

How is adiponectin involved in insulin receptor signaling?

Answer 8

• adiponectin binds to AdipoR1
• APPL1 (an adaptor protein) is recruited to AdipoR1
• APPL1/AdipoR1 interaction activates TSC1 and 2, engages PI3K and Akt to increase glucose transport, and activates AMPK, p38 MAPK, Rab and increase GLUT4 translocation and glucose transport
• overall, causes increase in insulin sensitivity and glucose transport

Question 9

By what specific mechanism does adiponectin increase insulin sensitivity?

Answer 9

activating AMPK, which activates TCS1 and 2, resulting in less S6K phosphorylation of the serines on the insulin receptor and IRS1

Question 10

How does obesity cause defective insulin action?

Answer 10

obesity causes: hyperinsulinemia and increase FFA

increase FFA decreases adiponectin levels, which causes insulin resistance

hyperinsulinemia leads to decreased adiponectin receptor expression, and therefore adiponectin resistance, which causes more insulin resistance

insulin resistance causes further hyperinsulinemia, creating a vicious cycle

Question 11

How does APPL2 effect the action of adiponectin?

Answer 11

APPL2 inhibits the APPL1/AdipoR1 interaction, therefore decreasing insulin sensitivity

Question 12

The one function that almost all adipokines have in common is…

Answer 12

impair insulin signaling/causes insulin resistance

Question 13

Other than adiponectin, what are some of the other adipokines?

Answer 13

leptin
TNF-a
resistin
IL-6
PAI-1
angiotensinogen

Question 14

MAP is a measure of…

Answer 14

average aortic pressure

Question 15

Increased MAP can be derived from…

Answer 15

increase SBP or DBP
increase in CO (due to water retention)
increase in TPR (constriction of blood vessels)

Question 16

What is the boundary for a true hypertensive state?

Answer 16

SBP > 135-140
DBP > 85-90

Question 17

True or False: the majority of hypertensive subjects are glucose intolerant or obese

Answer 17

True

Question 18

What are some anti-hypertensives that do not have a negative impact on insulin sensitivity?

Answer 18

B-blockers
Renin inhibitors
ACE inhibitors
AT II receptor blockers

Question 19

In non-diabetics, how do hypertension and hyperinsulinemia correlate?

Answer 19

As hyperinsulinemia increases, hypertension also increases

Question 20

How can hyperinsulinemia be connected to hypertension in the metabolic syndrome?

Answer 20

increase SNS activity leads to vasoconstriction, increase ENaC leads to Na+ retention, increase NHS (salt sensitivity) leads to Na+ retention, increase vascular smooth muscle cell proliferation and FFAs leads to vascular rigidity and constrictor responses

all of those things cause hypertension

Question 21

How does overactivity of the RAA system cause hypertension?

Answer 21

• increase SNS activity stimulates renin secretion
• renin converts angiotensinogen to ANG1, angiotensin converting enzyme (ACE) converts ANG1 to ANG2
• ANG2 acts by increasing water reabsorption and vasoconstriction, both increasing BP

Question 22

How can hypertension due to an overactive RAA system be treated?

Answer 22

ACE inhibitors, ANG receptor blockers, or new drugs that directly inhibit the activity of renin

Question 23

Besides its actions at the kidney, how can ANG2 be associated with insulin resistance?

Answer 23

ANG2 binding leads to oxidative stress and antagonism of insulin signaling and reduced GLUT4 translocation